ID TNFA_HUMAN Reviewed; 233 AA. AC P01375; O43647; Q9P1Q2; Q9UIV3; DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot. DT 21-JUL-1986, sequence version 1. DT 04-NOV-2026, entry version 284. DE RecName: Full=Tumor necrosis factor; DE AltName: Full=Cachectin; DE AltName: Full=TNF-alpha; DE AltName: Full=Tumor necrosis factor ligand superfamily member 2; DE Short=TNF-a; DE Contains: DE RecName: Full=Tumor necrosis factor, membrane form; DE AltName: Full=N-terminal fragment; DE Short=NTF; DE Contains: DE RecName: Full=Intracellular domain 1; DE Short=ICD1; DE Contains: DE RecName: Full=Intracellular domain 2; DE Short=ICD2; DE Contains: DE RecName: Full=C-domain 1; DE Contains: DE RecName: Full=C-domain 2; DE Contains: DE RecName: Full=Tumor necrosis factor, soluble form; DE Flags: Precursor; GN Name=TNF; Synonyms=TNFA, TNFSF2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=3555974; DOI=10.1101/sqb.1986.051.01.073; RA Nedospasov S.A., Shakhov A.N., Turetskaya R.L., Mett V.A., Azizov M.M., RA Georgiev G.P., Korobko V.G., Dobrynin V.N., Filippov S.A., Bystrov N.S., RA Boldyreva E.F., Chuvpilo S.A., Chumakov A.M., Shingarova L.N., RA Ovchinnikov Y.A.; RT "Tandem arrangement of genes coding for tumor necrosis factor (TNF-alpha) RT and lymphotoxin (TNF-beta) in the human genome."; RL Cold Spring Harb. Symp. Quant. Biol. 51:611-624(1986). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], FUNCTION, AND SUBCELLULAR RP LOCATION. RX PubMed=6392892; DOI=10.1038/312724a0; RA Pennica D., Nedwin G.E., Hayflick J.S., Seeburg P.H., Derynck R., RA Palladino M.A., Kohr W.J., Aggarwal B.B., Goeddel D.V.; RT "Human tumour necrosis factor: precursor structure, expression and homology RT to lymphotoxin."; RL Nature 312:724-729(1984). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND FUNCTION. RX PubMed=3883195; DOI=10.1038/313803a0; RA Shirai T., Yamaguchi H., Ito H., Todd C.W., Wallace R.B.; RT "Cloning and expression in Escherichia coli of the gene for human tumour RT necrosis factor."; RL Nature 313:803-806(1985). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. RX PubMed=2995927; DOI=10.1093/nar/13.17.6361; RA Nedwin G.E., Naylor S.L., Sakaguchi A.Y., Smith D.H., Jarrett-Nedwin J., RA Pennica D., Goeddel D.V., Gray P.W.; RT "Human lymphotoxin and tumor necrosis factor genes: structure, homology and RT chromosomal localization."; RL Nucleic Acids Res. 13:6361-6373(1985). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=3856324; DOI=10.1126/science.3856324; RA Wang A.M., Creasey A.A., Ladner M.B., Lin L.S., Strickler J., RA van Arsdell J.N., Yamamoto R., Mark D.F.; RT "Molecular cloning of the complementary DNA for human tumor necrosis RT factor."; RL Science 228:149-154(1985). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND SUBCELLULAR LOCATION. RX PubMed=3932069; DOI=10.1111/j.1432-1033.1985.tb09226.x; RA Marmenout A., Fransen L., Tavernier J., van der Heyden J., Tizard R., RA Kawashima E., Shaw A., Johnson M.J., Semon D., Mueller R., RA Ruysschaert M.-R., van Vliet A., Fiers W.; RT "Molecular cloning and expression of human tumor necrosis factor and RT comparison with mouse tumor necrosis factor."; RL Eur. J. Biochem. 152:515-522(1985). RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=8499947; DOI=10.1038/ng0293-137; RA Iris F.J.M., Bougueleret L., Prieur S., Caterina D., Primas G., Perrot V., RA Jurka J., Rodriguez-Tome P., Claverie J.-M., Dausset J., Cohen D.; RT "Dense Alu clustering and a potential new member of the NF kappa B family RT within a 90 kilobase HLA class III segment."; RL Nat. Genet. 3:137-145(1993). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=10202016; RA Neville M.J., Campbell R.D.; RT "A new member of the Ig superfamily and a V-ATPase G subunit are among the RT predicted products of novel genes close to the TNF locus in the human RT MHC."; RL J. Immunol. 162:4745-4754(1999). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14656967; DOI=10.1101/gr.1736803; RA Xie T., Rowen L., Aguado B., Ahearn M.E., Madan A., Qin S., Campbell R.D., RA Hood L.; RT "Analysis of the gene-dense major histocompatibility complex class III RT region and its comparison to mouse."; RL Genome Res. 13:2621-2636(2003). RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Shiina S., Tamiya G., Oka A., Inoko H.; RT "Homo sapiens 2,229,817bp genomic DNA of 6p21.3 HLA class I region."; RL Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Shiina T., Ota M., Katsuyama Y., Hashimoto N., Inoko H.; RT "Genome diversity in HLA: a new strategy for detection of genetic RT polymorphisms in expressed genes within the HLA class III and class I RT regions."; RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases. RN [12] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG SeattleSNPs variation discovery resource; RL Submitted (DEC-2001) to the EMBL/GenBank/DDBJ databases. RN [13] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LEU-84. RG NIEHS SNPs program; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [14] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Blood; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [15] RP PROTEIN SEQUENCE OF 77-99, AND GLYCOSYLATION AT SER-80. RX PubMed=8631363; DOI=10.1111/j.1432-1033.1996.00431.x; RA Takakura-Yamamoto R., Yamamoto S., Fukuda S., Kurimoto M.; RT "O-glycosylated species of natural human tumor-necrosis factor-alpha."; RL Eur. J. Biochem. 235:431-437(1996). RN [16] RP NUCLEOTIDE SEQUENCE [MRNA] OF 77-233. RA Jang J.S., Kim B.E.; RL Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases. RN [17] RP NUCLEOTIDE SEQUENCE [MRNA] OF 84-214. RC TISSUE=Prostatic carcinoma; RA Shao C., Yan W., Zhu F., Yue W., Chai Y., Zhao Z., Wang C.; RL Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases. RN [18] RP PHOSPHORYLATION (MEMBRANE FORM). RX PubMed=8597870; RA Pocsik E., Duda E., Wallach D.; RT "Phosphorylation of the 26 kDa TNF precursor in monocytic cells and in RT transfected HeLa cells."; RL J. Inflamm. 45:152-160(1995). RN [19] RP PHOSPHORYLATION BY CK1, AND DEPHOSPHORYLATION. RX PubMed=10205166; DOI=10.1093/emboj/18.8.2119; RA Watts A.D., Hunt N.H., Wanigasekara Y., Bloomfield G., Wallach D., RA Roufogalis B.D., Chaudhri G.; RT "A casein kinase I motif present in the cytoplasmic domain of members of RT the tumour necrosis factor ligand family is implicated in 'reverse RT signalling'."; RL EMBO J. 18:2119-2126(1999). RN [20] RP MUTAGENESIS. RX PubMed=2009860; DOI=10.1002/j.1460-2075.1991.tb08015.x; RA Ostade X.V., Tavernier J., Prange T., Fiers W.; RT "Localization of the active site of human tumour necrosis factor (hTNF) by RT mutational analysis."; RL EMBO J. 10:827-836(1991). RN [21] RP MYRISTOYLATION AT LYS-19 AND LYS-20. RX PubMed=1402651; DOI=10.1084/jem.176.4.1053; RA Stevenson F.T., Bursten S.L., Locksley R.M., Lovett D.H.; RT "Myristyl acylation of the tumor necrosis factor alpha precursor on RT specific lysine residues."; RL J. Exp. Med. 176:1053-1062(1992). RN [22] RP CLEAVAGE BY ADAM17. RX PubMed=9034191; DOI=10.1038/385733a0; RA Moss M.L., Jin S.-L.C., Milla M.E., Burkhart W., Carter H.L., Chen W.-J., RA Clay W.C., Didsbury J.R., Hassler D., Hoffman C.R., Kost T.A., RA Lambert M.H., Leesnitzer M.A., McCauley P., McGeehan G., Mitchell J., RA Moyer M., Pahel G., Rocque W., Overton L.K., Schoenen F., Seaton T., RA Su J.-L., Warner J., Willard D., Becherer J.D.; RT "Cloning of a disintegrin metalloproteinase that processes precursor RT tumour-necrosis factor-alpha."; RL Nature 385:733-736(1997). RN [23] RP FUNCTION. RX PubMed=9435233; DOI=10.1073/pnas.95.2.570; RA Grell M., Wajant H., Zimmermann G., Scheurich P.; RT "The type 1 receptor (CD120a) is the high-affinity receptor for soluble RT tumor necrosis factor."; RL Proc. Natl. Acad. Sci. U.S.A. 95:570-575(1998). RN [24] RP POLYMORPHISM, AND INVOLVEMENT IN SUSCEPTIBILITY TO MALARIA. RX PubMed=10369255; DOI=10.1038/9649; RA Knight J.C., Udalova I., Hill A.V., Greenwood B.M., Peshu N., Marsh K., RA Kwiatkowski D.; RT "A polymorphism that affects OCT-1 binding to the TNF promoter region is RT associated with severe malaria."; RL Nat. Genet. 22:145-150(1999). RN [25] RP FUNCTION. RX PubMed=11592999; DOI=10.1073/pnas.211178398; RA Carter P.H., Scherle P.A., Muckelbauer J.K., Voss M.E., Liu R.Q., RA Thompson L.A., Tebben A.J., Solomon K.A., Lo Y.C., Li Z., Strzemienski P., RA Yang G., Falahatpisheh N., Xu M., Wu Z., Farrow N.A., Ramnarayan K., RA Wang J., Rideout D., Yalamoori V., Domaille P., Underwood D.J., RA Trzaskos J.M., Friedman S.M., Newton R.C., Decicco C.P.; RT "Photochemically enhanced binding of small molecules to the tumor necrosis RT factor receptor-1 inhibits the binding of TNF-alpha."; RL Proc. Natl. Acad. Sci. U.S.A. 98:11879-11884(2001). RN [26] RP INVOLVEMENT IN PSORIATIC ARTHRITIS SUSCEPTIBILITY. RX PubMed=12746914; DOI=10.1002/art.10935; RA Balding J., Kane D., Livingstone W., Mynett-Johnson L., Bresnihan B., RA Smith O., FitzGerald O.; RT "Cytokine gene polymorphisms: association with psoriatic arthritis RT susceptibility and severity."; RL Arthritis Rheum. 48:1408-1413(2003). RN [27] RP FUNCTION. RX PubMed=12794819; DOI=10.1002/art.11143; RA Nakahara H., Song J., Sugimoto M., Hagihara K., Kishimoto T., Yoshizaki K., RA Nishimoto N.; RT "Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial RT growth factor production in rheumatoid arthritis."; RL Arthritis Rheum. 48:1521-1529(2003). RN [28] RP INVOLVEMENT IN SUSCEPTIBILITY TO HBV INFECTION. RX PubMed=12915457; DOI=10.1093/hmg/ddg262; RA Kim Y.J., Lee H.-S., Yoon J.-H., Kim C.Y., Park M.H., Kim L.H., Park B.L., RA Shin H.D.; RT "Association of TNF-alpha promoter polymorphisms with the clearance of RT hepatitis B virus infection."; RL Hum. Mol. Genet. 12:2541-2546(2003). RN [29] RP FUNCTION OF TNF INTRACELLULAR DOMAIN, CLEAVAGE BY SPPL2A AND SPPL2B, AND RP SUBCELLULAR LOCATION. RX PubMed=16829952; DOI=10.1038/ncb1440; RA Friedmann E., Hauben E., Maylandt K., Schleeger S., Vreugde S., RA Lichtenthaler S.F., Kuhn P.H., Stauffer D., Rovelli G., Martoglio B.; RT "SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in RT activated dendritic cells to trigger IL-12 production."; RL Nat. Cell Biol. 8:843-848(2006). RN [30] RP CLEAVAGE BY SPPL2A AND SPPL2B, CLEAVAGE SITE, SUBCELLULAR LOCATION, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=16829951; DOI=10.1038/ncb1450; RA Fluhrer R., Grammer G., Israel L., Condron M.M., Haffner C., Friedmann E., RA Bohland C., Imhof A., Martoglio B., Teplow D.B., Haass C.; RT "A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD RT aspartyl protease SPPL2b."; RL Nat. Cell Biol. 8:894-896(2006). RN [31] RP FUNCTION. RX PubMed=22517918; DOI=10.1189/jlb.1211623; RA Jinesh G.G., Chunduru S., Kamat A.M.; RT "Smac mimetic enables the anticancer action of BCG-stimulated neutrophils RT through TNF-alpha but not through TRAIL and FasL."; RL J. Leukoc. Biol. 92:233-244(2012). RN [32] RP MYRISTOYLATION AT LYS-19 AND LYS-20, DEMYRISTOYLATION AT LYS-19 AND LYS-20, RP SUBCELLULAR LOCATION (TUMOR NECROSIS FACTOR, SOLUBLE FORM), AND MUTAGENESIS RP OF 19-LYS-LYS-20. RX PubMed=23552949; DOI=10.1038/nature12038; RA Jiang H., Khan S., Wang Y., Charron G., He B., Sebastian C., Du J., Kim R., RA Ge E., Mostoslavsky R., Hang H.C., Hao Q., Lin H.; RT "SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty RT acyl lysine."; RL Nature 496:110-113(2013). RN [33] RP FUNCTION. RX PubMed=23396208; DOI=10.1038/nm.3085; RA Nie H., Zheng Y., Li R., Guo T.B., He D., Fang L., Liu X., Xiao L., RA Chen X., Wan B., Chin Y.E., Zhang J.Z.; RT "Phosphorylation of FOXP3 controls regulatory T cell function and is RT inhibited by TNF-alpha in rheumatoid arthritis."; RL Nat. Med. 19:322-328(2013). RN [34] RP INVOLVEMENT IN IMD127. RX PubMed=39198650; DOI=10.1038/s41586-024-07866-3; RA Arias A.A., Neehus A.L., Ogishi M., Meynier V., Krebs A., Lazarov T., RA Lee A.M., Arango-Franco C.A., Yang R., Orrego J., Corcini Berndt M., RA Rojas J., Li H., Rinchai D., Erazo-Borras L., Han J.E., Pillay B., RA Ponsin K., Chaldebas M., Philippot Q., Bohlen J., Rosain J., Le Voyer T., RA Janotte T., Amarajeeva K., Soudee C., Brollo M., Wiegmann K., Marquant Q., RA Seeleuthner Y., Lee D., Laine C., Kloos D., Bailey R., Bastard P., RA Keating N., Rapaport F., Khan T., Moncada-Velez M., Carmona M.C., RA Obando C., Alvarez J., Catano J.C., Martinez-Rosado L.L., Sanchez J.P., RA Tejada-Giraldo M., L'Honneur A.S., Agudelo M.L., Perez-Zapata L.J., RA Arboleda D.M., Alzate J.F., Cabarcas F., Zuluaga A., Pelham S.J., RA Ensser A., Schmidt M., Velasquez-Lopera M.M., Jouanguy E., Puel A., RA Kroenke M., Ghirardello S., Borghesi A., Pahari S., Boisson B., RA Pittaluga S., Ma C.S., Emile J.F., Notarangelo L.D., Tangye S.G., Marr N., RA Lachmann N., Salvator H., Schlesinger L.S., Zhang P., Glickman M.S., RA Nathan C.F., Geissmann F., Abel L., Franco J.L., Bustamante J., RA Casanova J.L., Boisson-Dupuis S.; RT "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."; RL Nature 633:417-425(2024). RN [35] RP X-RAY CRYSTALLOGRAPHY, AND SUBUNIT. RX PubMed=2922050; DOI=10.1038/338225a0; RA Jones E.Y., Stuart D.I., Walker N.P.; RT "Structure of tumour necrosis factor."; RL Nature 338:225-228(1989). RN [36] RP X-RAY CRYSTALLOGRAPHY, AND SUBUNIT. RX PubMed=1964681; DOI=10.1242/jcs.1990.supplement_13.3; RA Jones E.Y., Stuart D.I., Walker N.P.; RT "The structure of tumour necrosis factor -- implications for biological RT function."; RL J. Cell Sci. Suppl. 13:11-18(1990). RN [37] RP X-RAY CRYSTALLOGRAPHY, AND SUBUNIT. RX PubMed=2551905; DOI=10.2210/pdb1tnf/pdb; RA Eck M.J., Sprang S.R.; RT "The structure of tumor necrosis factor-alpha at 2.6-A resolution. RT Implications for receptor binding."; RL J. Biol. Chem. 264:17595-17605(1989). RN [38] RP X-RAY CRYSTALLOGRAPHY OF MUTANT ARG-107. RX PubMed=9488135; DOI=10.1093/protein/10.10.1101; RA Reed C., Fu Z.Q., Wu J., Xue Y.N., Harrison R.W., Chen M.J., Weber I.T.; RT "Crystal structure of TNF-alpha mutant R31D with greater affinity for RT receptor R1 compared with R2."; RL Protein Eng. 10:1101-1107(1997). RN [39] RP X-RAY CRYSTALLOGRAPHY OF MUTANT SER-3. RX PubMed=9442056; DOI=10.1074/jbc.273.4.2153; RA Cha S.S., Kim J.S., Cho H.S., Shin N.K., Jeong W., Shin H.C., Kim Y.J., RA Hahn J.H., Oh B.H.; RT "High resolution crystal structure of a human tumor necrosis factor-alpha RT mutant with low systemic toxicity."; RL J. Biol. Chem. 273:2153-2160(1998). RN [40] {ECO:0007744|PDB:2AZ5} RP X-RAY CRYSTALLOGRAPHY, FUNCTION, ACTIVITY REGULATION, SUBUNIT, AND RP DISULFIDE BOND. RX PubMed=16284179; DOI=10.1126/science.1116304; RA He M.M., Smith A.S., Oslob J.D., Flanagan W.M., Braisted A.C., Whitty A., RA Cancilla M.T., Wang J., Lugovskoy A.A., Yoburn J.C., Fung A.D., RA Farrington G., Eldredge J.K., Day E.S., Cruz L.A., Cachero T.G., RA Miller S.K., Friedman J.E., Choong I.C., Cunningham B.C.; RT "Small-molecule inhibition of TNF-alpha."; RL Science 310:1022-1025(2005). RN [41] {ECO:0007744|PDB:7KPA, ECO:0007744|PDB:7KPB} RP X-RAY CRYSTALLOGRAPHY IN COMPLEX WITH TNFRSF1A, FUNCTION, AND ACTIVITY RP REGULATION. RX PubMed=33495445; DOI=10.1038/s41467-020-20825-6; RA Lightwood D.J., Munro R.J., Porter J., McMillan D., Carrington B., RA Turner A., Scott-Tucker A., Hickford E.S., Schmidt A., Fox D. III, RA Maloney A., Ceska T., Bourne T., O'Connell J., Lawson A.D.G.; RT "A conformation-selective monoclonal antibody against a small molecule- RT stabilised signalling-deficient form of TNF."; RL Nat. Commun. 12:583-583(2021). CC -!- FUNCTION: Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR, CC activating the tumor necrosis factor-mediated (TNF) signaling pathway CC (PubMed:16284179, PubMed:33495445, PubMed:3883195, PubMed:6392892, CC PubMed:9435233). The TNF signaling pathway acts as a master regulator CC of the immune system, which either (1) promotes cell survival and CC inflammation by activating the canonical NF-kappa-B pathway or (2) CC trigger programmed cell death (apoptosis and necroptosis) CC (PubMed:16284179). Impairs regulatory T-cells (Treg) function in CC individuals with rheumatoid arthritis via FOXP3 dephosphorylation: acts CC by up-regulating the expression of protein phosphatase 1 (PP1), which CC dephosphorylates the key 'Ser-418' residue of FOXP3, thereby CC inactivating FOXP3 and rendering Treg cells functionally defective CC (PubMed:23396208). Key mediator of cell death in the anticancer action CC of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic CC in the RT4v6 bladder cancer cell line (PubMed:16829952, CC PubMed:22517918, PubMed:23396208). Induces insulin resistance in CC adipocytes via inhibition of insulin-induced IRS1 tyrosine CC phosphorylation and insulin-induced glucose uptake (By similarity). CC Induces GKAP42 protein degradation in adipocytes which is partially CC responsible for TNF-induced insulin resistance (By similarity). Plays a CC role in angiogenesis by inducing VEGF production synergistically with CC IL1B and IL6 (PubMed:12794819). Promotes osteoclastogenesis and CC therefore mediates bone resorption (By similarity). CC {ECO:0000250|UniProtKB:P06804, ECO:0000269|PubMed:12794819, CC ECO:0000269|PubMed:16284179, ECO:0000269|PubMed:16829952, CC ECO:0000269|PubMed:22517918, ECO:0000269|PubMed:23396208, CC ECO:0000269|PubMed:33495445, ECO:0000269|PubMed:3883195, CC ECO:0000269|PubMed:6392892, ECO:0000269|PubMed:9435233}. CC -!- FUNCTION: [Tumor necrosis factor, soluble form]: Cytokine mainly CC secreted by macrophages that binds to TNFRSF1A/TNFR1 and CC TNFRSF1B/TNFBR, activating the tumor necrosis factor-mediated (TNF) CC signaling pathway (PubMed:11592999, PubMed:16284179, PubMed:33495445, CC PubMed:3883195, PubMed:6392892). The TNF signaling pathway acts as a CC master regulator of the immune system, which either (1) promotes cell CC survival and inflammation by activating the canonical NF-kappa-B CC pathway or (2) trigger programmed cell death (apoptosis and CC necroptosis) (PubMed:16284179). {ECO:0000269|PubMed:11592999, CC ECO:0000269|PubMed:16284179, ECO:0000269|PubMed:33495445, CC ECO:0000269|PubMed:3883195, ECO:0000269|PubMed:6392892}. CC -!- FUNCTION: [Intracellular domain 1]: The TNF intracellular domain (ICD) CC form induces IL12 production in dendritic cells. CC {ECO:0000269|PubMed:16829952}. CC -!- FUNCTION: [Intracellular domain 2]: The TNF intracellular domain (ICD) CC form induces IL12 production in dendritic cells. CC {ECO:0000269|PubMed:16829952}. CC -!- ACTIVITY REGULATION: [Tumor necrosis factor, soluble form]: Inhibited CC by a small composed of trifluoromethylphenyl indole and dimethyl CC chromone moieties linked by a dimethylamine spacer, which prevents CC binding to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR receptors CC (PubMed:16284179). Inhibited by small molecules UCB-8733 and UCB-9260 CC (PubMed:33495445). {ECO:0000269|PubMed:16284179, CC ECO:0000269|PubMed:33495445}. CC -!- SUBUNIT: Homotrimer. {ECO:0000269|PubMed:16284179, CC ECO:0000269|PubMed:1964681, ECO:0000269|PubMed:2551905, CC ECO:0000269|PubMed:2922050}. CC -!- INTERACTION: CC P01375; P05067: APP; NbExp=3; IntAct=EBI-359977, EBI-77613; CC P01375; Q92482: AQP3; NbExp=3; IntAct=EBI-359977, EBI-2808854; CC P01375; Q9BXK5: BCL2L13; NbExp=3; IntAct=EBI-359977, EBI-747430; CC P01375; Q6UXG8-3: BTNL9; NbExp=3; IntAct=EBI-359977, EBI-17953245; CC P01375; Q8IYJ2-2: C10orf67; NbExp=3; IntAct=EBI-359977, EBI-13381098; CC P01375; Q8WV48: CCDC107; NbExp=3; IntAct=EBI-359977, EBI-947033; CC P01375; Q6NSX1: CCDC70; NbExp=3; IntAct=EBI-359977, EBI-6873045; CC P01375; O95471: CLDN7; NbExp=3; IntAct=EBI-359977, EBI-740744; CC P01375; Q8IUN9: CLEC10A; NbExp=3; IntAct=EBI-359977, EBI-2873246; CC P01375; Q96BA8: CREB3L1; NbExp=3; IntAct=EBI-359977, EBI-6942903; CC P01375; P00387: CYB5R3; NbExp=3; IntAct=EBI-359977, EBI-1046040; CC P01375; Q5JX71: FAM209A; NbExp=3; IntAct=EBI-359977, EBI-18304435; CC P01375; O15552: FFAR2; NbExp=3; IntAct=EBI-359977, EBI-2833872; CC P01375; Q8TBE3: FNDC9; NbExp=3; IntAct=EBI-359977, EBI-12142257; CC P01375; Q9Y6K9: IKBKG; NbExp=7; IntAct=EBI-359977, EBI-81279; CC P01375; Q8N6L0: KASH5; NbExp=3; IntAct=EBI-359977, EBI-749265; CC P01375; Q8N386: LRRC25; NbExp=3; IntAct=EBI-359977, EBI-11304917; CC P01375; O43300: LRRTM2; NbExp=3; IntAct=EBI-359977, EBI-18096461; CC P01375; Q9HC36: MRM3; NbExp=3; IntAct=EBI-359977, EBI-1045440; CC P01375; O75459: PAGE1; NbExp=3; IntAct=EBI-359977, EBI-2559100; CC P01375; Q96RD7: PANX1; NbExp=3; IntAct=EBI-359977, EBI-7037612; CC P01375; Q8N4L2: PIP4P2; NbExp=3; IntAct=EBI-359977, EBI-2820617; CC P01375; Q53GL0: PLEKHO1; NbExp=3; IntAct=EBI-359977, EBI-949945; CC P01375; Q6ZMZ0: RNF19B; NbExp=3; IntAct=EBI-359977, EBI-2466594; CC P01375; P31949: S100A11; NbExp=4; IntAct=EBI-359977, EBI-701862; CC P01375; P80511: S100A12; NbExp=4; IntAct=EBI-359977, EBI-2823305; CC P01375; Q99584: S100A13; NbExp=3; IntAct=EBI-359977, EBI-721909; CC P01375; Q16585: SGCB; NbExp=3; IntAct=EBI-359977, EBI-5663627; CC P01375; Q15849: SLC14A2; NbExp=3; IntAct=EBI-359977, EBI-1573290; CC P01375; O14863: SLC30A4; NbExp=3; IntAct=EBI-359977, EBI-13918058; CC P01375; Q8WWF3: SSMEM1; NbExp=3; IntAct=EBI-359977, EBI-17280858; CC P01375; P27105: STOM; NbExp=3; IntAct=EBI-359977, EBI-1211440; CC P01375; Q16623: STX1A; NbExp=4; IntAct=EBI-359977, EBI-712466; CC P01375; O15393-2: TMPRSS2; NbExp=3; IntAct=EBI-359977, EBI-12345267; CC P01375; P01375: TNF; NbExp=3; IntAct=EBI-359977, EBI-359977; CC P01375; P19438: TNFRSF1A; NbExp=32; IntAct=EBI-359977, EBI-299451; CC P01375; P20333: TNFRSF1B; NbExp=5; IntAct=EBI-359977, EBI-358983; CC P01375; Q9H7M9: VSIR; NbExp=3; IntAct=EBI-359977, EBI-744988; CC P01375; Q96S55: WRNIP1; NbExp=6; IntAct=EBI-359977, EBI-2513471; CC P01375; Q6PEW1: ZCCHC12; NbExp=3; IntAct=EBI-359977, EBI-748373; CC P01375; Q9DHW0: 2L; Xeno; NbExp=2; IntAct=EBI-359977, EBI-15810797; CC P01375; O89110: Casp8; Xeno; NbExp=2; IntAct=EBI-359977, EBI-851690; CC P01375; Q8UYL3: crmE; Xeno; NbExp=3; IntAct=EBI-359977, EBI-7539950; CC P01375; O88351: Ikbkb; Xeno; NbExp=3; IntAct=EBI-359977, EBI-447960; CC P01375; Q60855: Ripk1; Xeno; NbExp=4; IntAct=EBI-359977, EBI-529119; CC P01375; Q60769: Tnfaip3; Xeno; NbExp=2; IntAct=EBI-359977, EBI-646595; CC P01375; P25118: Tnfrsf1a; Xeno; NbExp=4; IntAct=EBI-359977, EBI-518014; CC P01375; Q3U0V2: Tradd; Xeno; NbExp=2; IntAct=EBI-359977, EBI-1544032; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:16829952}; CC Single-pass type II membrane protein {ECO:0000255}. CC -!- SUBCELLULAR LOCATION: [Tumor necrosis factor, membrane form]: Membrane CC {ECO:0000269|PubMed:16829952}; Single-pass type II membrane protein CC {ECO:0000255}. CC -!- SUBCELLULAR LOCATION: [Tumor necrosis factor, soluble form]: Secreted CC {ECO:0000269|PubMed:23552949, ECO:0000269|PubMed:3932069}. CC -!- SUBCELLULAR LOCATION: [C-domain 1]: Secreted CC {ECO:0000269|PubMed:16829951}. CC -!- SUBCELLULAR LOCATION: [C-domain 2]: Secreted CC {ECO:0000269|PubMed:16829951}. CC -!- PTM: The soluble form derives from the membrane form by proteolytic CC processing by ADAM17 (PubMed:9034191). The membrane-bound form is CC further proteolytically processed by SPPL2A or SPPL2B through regulated CC intramembrane proteolysis producing TNF intracellular domains (ICD1 and CC ICD2) released in the cytosol and TNF C-domain 1 and C-domain 2 CC secreted into the extracellular space (PubMed:16829951, CC PubMed:16829952). {ECO:0000269|PubMed:16829951, CC ECO:0000269|PubMed:16829952, ECO:0000269|PubMed:9034191}. CC -!- PTM: [Tumor necrosis factor, membrane form]: The membrane form, but not CC the soluble form, is phosphorylated on serine residues CC (PubMed:10205166, PubMed:8597870). Dephosphorylation of the membrane CC form occurs by binding to soluble TNFRSF1A/TNFR1 (PubMed:10205166, CC PubMed:8597870). {ECO:0000269|PubMed:10205166, CC ECO:0000269|PubMed:8597870}. CC -!- PTM: O-glycosylated; glycans contain galactose, N-acetylgalactosamine CC and N-acetylneuraminic acid. {ECO:0000269|PubMed:8631363}. CC -!- PTM: [Tumor necrosis factor, soluble form]: The soluble form is CC demyristoylated at Lys-19 and Lys-20 by SIRT6, promoting its secretion. CC {ECO:0000269|PubMed:23552949}. CC -!- POLYMORPHISM: Genetic variations in TNF influence susceptibility to CC hepatitis B virus (HBV) infection [MIM:610424]. CC {ECO:0000269|PubMed:12915457}. CC -!- POLYMORPHISM: Genetic variations in TNF are involved in susceptibility CC to malaria [MIM:611162]. {ECO:0000269|PubMed:10369255}. CC -!- DISEASE: Psoriatic arthritis (PSORAS) [MIM:607507]: An inflammatory, CC seronegative arthritis associated with psoriasis. It is a heterogeneous CC disorder ranging from a mild, non-destructive disease to a severe, CC progressive, erosive arthropathy. Five types of psoriatic arthritis CC have been defined: asymmetrical oligoarthritis characterized by primary CC involvement of the small joints of the fingers or toes; asymmetrical CC arthritis which involves the joints of the extremities; symmetrical CC polyarthritis characterized by a rheumatoid like pattern that can CC involve hands, wrists, ankles, and feet; arthritis mutilans, which is a CC rare but deforming and destructive condition; arthritis of the CC sacroiliac joints and spine (psoriatic spondylitis). CC {ECO:0000269|PubMed:12746914}. Note=Disease susceptibility is CC associated with variants affecting the gene represented in this entry. CC -!- DISEASE: Immunodeficiency 127 (IMD127) [MIM:620977]: An autosomal CC recessive immunologic disorder characterized by increased CC susceptibility to pulmonary infection with Mycobacterium tuberculosis. CC Affected individuals develop recurrent pulmonary tuberculosis, but have CC no adverse reaction to live BCG vaccination. CC {ECO:0000269|PubMed:39198650}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the tumor necrosis factor family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAF71992.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=CAA75070.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Tumor necrosis factor alpha entry; CC URL="https://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha"; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/319/TNFa"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M16441; AAA61200.1; -; Genomic_DNA. DR EMBL; X02910; CAA26669.1; -; Genomic_DNA. DR EMBL; X01394; CAA25650.1; -; mRNA. DR EMBL; M10988; AAA61198.1; -; mRNA. DR EMBL; M26331; AAA36758.1; -; Genomic_DNA. DR EMBL; Z15026; CAA78745.1; -; Genomic_DNA. DR EMBL; Y14768; CAA75070.1; ALT_SEQ; Genomic_DNA. DR EMBL; AF129756; AAD18091.1; -; Genomic_DNA. DR EMBL; BA000025; BAB63396.1; -; Genomic_DNA. DR EMBL; AB088112; BAC54944.1; -; Genomic_DNA. DR EMBL; AY066019; AAL47581.1; -; Genomic_DNA. DR EMBL; AY214167; AAO21132.1; -; Genomic_DNA. DR EMBL; BC028148; AAH28148.1; -; mRNA. DR EMBL; AF043342; AAC03542.1; -; mRNA. DR EMBL; AF098751; AAF71992.1; ALT_FRAME; mRNA. DR CCDS; CCDS4702.1; -. DR PIR; A93585; QWHUN. DR RefSeq; NP_000585.2; NM_000594.4. DR PDB; 1A8M; X-ray; 2.30 A; A/B/C=77-233. DR PDB; 1TNF; X-ray; 2.60 A; A/B/C=77-233. DR PDB; 21TV; EM; 6.19 A; B/C/D=77-233. DR PDB; 21TW; EM; 2.43 A; B/C/D=77-233. DR PDB; 2AZ5; X-ray; 2.10 A; A/B/C/D=86-233. DR PDB; 2E7A; X-ray; 1.80 A; A/B/C=77-233. DR PDB; 2TUN; X-ray; 3.10 A; A/B/C/D/E/F=77-233. DR PDB; 2ZJC; X-ray; 2.50 A; A/B/C=77-233. DR PDB; 2ZPX; X-ray; 2.83 A; A/B/C=77-233. DR PDB; 3ALQ; X-ray; 3.00 A; A/B/C/D/E/F=77-233. DR PDB; 3IT8; X-ray; 2.80 A; A/B/C/G/H/I=82-233. DR PDB; 3L9J; X-ray; 2.10 A; T=85-233. DR PDB; 3WD5; X-ray; 3.10 A; A=77-233. DR PDB; 4G3Y; X-ray; 2.60 A; C=77-233. DR PDB; 4TSV; X-ray; 1.80 A; A=84-233. DR PDB; 4TWT; X-ray; 2.85 A; A/B/C/D=77-233. DR PDB; 4Y6O; X-ray; 1.60 A; C/D=17-23. DR PDB; 5M2I; X-ray; 2.15 A; A/B/C/D/E/F=77-233. DR PDB; 5M2J; X-ray; 1.90 A; A=77-233. DR PDB; 5M2M; X-ray; 2.30 A; A/B/C/G/I/M=77-233. DR PDB; 5MU8; X-ray; 3.00 A; A/B/C/D/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y/Z/a/b/c/d/e=77-233. DR PDB; 5TSW; X-ray; 2.50 A; A/B/C/D/E/F=84-233. DR PDB; 5UUI; X-ray; 1.40 A; A=77-233. DR PDB; 5WUX; X-ray; 2.90 A; E/F/G=77-233. DR PDB; 5YOY; X-ray; 2.73 A; A/B/C/J/K/L=76-233. DR PDB; 6OOY; X-ray; 2.50 A; A/B/C=77-233. DR PDB; 6OOZ; X-ray; 2.80 A; A/B/C=77-233. DR PDB; 6OP0; X-ray; 2.55 A; A/B/C=77-233. DR PDB; 6RMJ; X-ray; 2.65 A; A/B/C=77-233. DR PDB; 6X81; X-ray; 2.81 A; A/B/C/D/E/F=77-233. DR PDB; 6X82; X-ray; 2.75 A; A/B/C/D/E/F=77-233. DR PDB; 6X83; X-ray; 2.83 A; A/B/C/D/E/F=77-233. DR PDB; 6X85; X-ray; 2.85 A; A/B/C/D/E/F=77-233. DR PDB; 6X86; X-ray; 2.93 A; A/B/C/D/E/F=77-233. DR PDB; 7ASY; NMR; -; A=28-60. DR PDB; 7AT7; NMR; -; A=28-60. DR PDB; 7ATB; NMR; -; A=28-60. DR PDB; 7JRA; X-ray; 2.10 A; A/B/C=77-233. DR PDB; 7KP9; X-ray; 2.15 A; A/B/C=77-233. DR PDB; 7KPA; X-ray; 2.30 A; A/B/C=77-233. DR PDB; 7KPB; X-ray; 3.00 A; A/B/C=77-233. DR PDB; 7QLF; NMR; -; A=178-191. DR PDB; 7TA3; X-ray; 2.50 A; B/D=77-233. DR PDB; 7TA6; X-ray; 2.67 A; A/B/C/D/E/F/G/H=77-233. DR PDB; 8Z8M; X-ray; 2.59 A; A/C/E/G/I/K=77-233. DR PDB; 8ZUI; EM; 2.56 A; A/B/C/G/H/I=77-233. DR PDB; 9BN7; X-ray; 1.92 A; A/B/C=77-233. DR PDB; 9DJW; X-ray; 3.31 A; 2/3/4/A/B/C/G/H/I/M/N/O/S/T/U/Y/Z/a/e/f/g/k/l/m/q/r/s/w/x/y=78-233. DR PDB; 9OJO; X-ray; 1.36 A; A/B/C=77-233. DR PDB; 9OJS; X-ray; 1.85 A; A/B/C=77-233. DR PDB; 9OJY; X-ray; 2.16 A; A/B/C/D/E/F=77-233. DR PDB; 9OK6; X-ray; 2.78 A; A/B/C/D/E/F=77-233. DR AlphaFoldDB; P01375; -. DR EMDB; EMD-60484; -. DR EMDB; EMD-60489; -. DR EMDB; EMD-60490; -. DR EMDB; EMD-60491; -. DR EMDB; EMD-60494; -. DR EMDB; EMD-60497; -. DR EMDB; EMD-60549; -. DR EMDB; EMD-67993; -. DR EMDB; EMD-67994; -. DR MDposit; P01375; -. DR MDRepo; P01375; -. DR SMR; P01375; -. DR BioGRID; 112979; 350. DR ComplexPortal; CPX-2805; sTNF:TNR1B receptor-ligand complex. DR ComplexPortal; CPX-8826; Soluble tumor necrosis factor complex. DR ComplexPortal; CPX-8931; Transmembrane tumor necrosis factor complex. DR CORUM; P01375; -. DR DIP; DIP-2895N; -. DR FunCoup; P01375; 1671. DR IntAct; P01375; 150. DR NDEx; IQUERY-CP-TNF; 123 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000398698; -. DR BindingDB; P01375; -. DR ChEMBL; CHEMBL1825; -. DR DrugBank; DB07145; (2R)-N-HYDROXY-2-[(3S)-3-METHYL-3-{4-[(2-METHYLQUINOLIN-4-YL)METHOXY]PHENYL}-2-OXOPYRROLIDIN-1-YL]PROPANAMIDE. DR DrugBank; DB00051; Adalimumab. DR DrugBank; DB04956; Afelimomab. DR DrugBank; DB05879; AME-527. DR DrugBank; DB01427; Amrinone. DR DrugBank; DB05054; AN0128. DR DrugBank; DB05767; Andrographolide. DR DrugBank; DB05513; Atiprimod. DR DrugBank; DB16101; Baicalein. DR DrugBank; DB11752; Bryostatin 1. DR DrugBank; DB20694; Camobucol. DR DrugBank; DB18736; Celastrol. DR DrugBank; DB08904; Certolizumab pegol. DR DrugBank; DB00608; Chloroquine. DR DrugBank; DB01407; Clenbuterol. DR DrugBank; DB05744; CRx-139. DR DrugBank; DB05758; CYT007-TNFQb. DR DrugBank; DB06444; Dexanabinol. DR DrugBank; DB12140; Dilmapimod. DR DrugBank; DB00668; Epinephrine. DR DrugBank; DB00005; Etanercept. DR DrugBank; DB05869; Ethyl pyruvate. DR DrugBank; DB10770; Foreskin fibroblast (neonatal). DR DrugBank; DB10772; Foreskin keratinocyte (neonatal). DR DrugBank; DB13751; Glycyrrhizic acid. DR DrugBank; DB06674; Golimumab. DR DrugBank; DB00065; Infliximab. DR DrugBank; DB02325; Isopropyl alcohol. DR DrugBank; DB12193; Lenabasum. DR DrugBank; DB00480; Lenalidomide. DR DrugBank; DB12598; Nafamostat. DR DrugBank; DB05303; OMS-103HP. DR DrugBank; DB06495; Onercept. DR DrugBank; DB11669; Ortataxel. DR DrugBank; DB00806; Pentoxifylline. DR DrugBank; DB05992; Plinabulin. DR DrugBank; DB05218; PN0621. DR DrugBank; DB09221; Polaprezinc. DR DrugBank; DB08910; Pomalidomide. DR DrugBank; DB05968; PR-104. DR DrugBank; DB01411; Pranlukast. DR DrugBank; DB00852; Pseudoephedrine. DR DrugBank; DB06566; RDP58. DR DrugBank; DB05207; SD118. DR DrugBank; DB17894; Senlizumab. DR DrugBank; DB05412; Talmapimod. DR DrugBank; DB01041; Thalidomide. DR DrugBank; DB04297; Trichostatin A. DR DrugBank; DB05470; VX-702. DR DrugBank; DB16454; XPro1595. DR DrugBank; DB05017; YSIL6. DR DrugCentral; P01375; -. DR GlyConnect; P01375; 3 O-Linked glycans (1 site). DR GlyCosmos; P01375; 1 site, 5 glycans. DR GlyGen; P01375; 1 site, 5 O-linked glycans (1 site). DR iPTMnet; P01375; -. DR PhosphoSitePlus; P01375; -. DR SwissPalm; P01375; -. DR BioMuta; TNF; -. DR DMDM; 135934; -. DR MassIVE; P01375; -. DR PaxDb; 9606-ENSP00000398698; -. DR PeptideAtlas; P01375; -. DR ProteomicsDB; 51379; -. DR ABCD; P01375; 210 sequenced antibodies. DR Antibodypedia; 27196; 5756 antibodies from 61 providers. DR DNASU; 7124; -. DR Ensembl; ENST00000376122.3; ENSP00000365290.3; ENSG00000204490.3. DR Ensembl; ENST00000383496.4; ENSP00000372988.4; ENSG00000206439.5. DR Ensembl; ENST00000412275.2; ENSP00000392858.2; ENSG00000228321.3. DR Ensembl; ENST00000420425.2; ENSP00000410668.2; ENSG00000228849.3. DR Ensembl; ENST00000443707.2; ENSP00000389492.2; ENSG00000230108.3. DR Ensembl; ENST00000448781.2; ENSP00000389490.2; ENSG00000223952.3. DR Ensembl; ENST00000449264.3; ENSP00000398698.2; ENSG00000232810.5. DR GeneID; 7124; -. DR KEGG; hsa:7124; -. DR MANE-Select; ENST00000449264.3; ENSP00000398698.2; NM_000594.4; NP_000585.2. DR AGR; HGNC:11892; -. DR ClinPGx; PA435; -. DR CTD; 7124; -. DR DisGeNET; 7124; -. DR GeneCards; TNF; -. DR HGNC; HGNC:11892; TNF. DR HPA; ENSG00000232810; Tissue enhanced (bone marrow, lymphoid tissue). DR MalaCards; TNF; -. DR MIM; 191160; gene. DR MIM; 607507; phenotype. DR MIM; 610424; phenotype. DR MIM; 611162; phenotype. DR MIM; 620977; phenotype. DR OpenTargets; ENSG00000232810; -. DR VEuPathDB; HostDB:ENSG00000232810; -. DR eggNOG; ENOG502S4K8; Eukaryota. DR GeneTree; ENSGT01060000248544; -. DR HOGENOM; CLU_070352_3_1_1; -. DR InParanoid; P01375; -. DR OMA; AAIKSPC; -. DR OrthoDB; 9940698at2759; -. DR PAN-GO; P01375; 7 GO annotations based on evolutionary models. DR PhylomeDB; P01375; -. DR PathwayCommons; P01375; -. DR Reactome; R-HSA-381340; Transcriptional regulation of white adipocyte differentiation. DR Reactome; R-HSA-5357786; TNFR1-induced proapoptotic signaling. DR Reactome; R-HSA-5357905; Regulation of TNFR1 signaling. DR Reactome; R-HSA-5357956; TNFR1-induced NF-kappa-B signaling pathway. DR Reactome; R-HSA-5626978; TNFR1-mediated ceramide production. DR Reactome; R-HSA-5668541; TNFR2 non-canonical NF-kB pathway. DR Reactome; R-HSA-6783783; Interleukin-10 signaling. DR Reactome; R-HSA-6785807; Interleukin-4 and Interleukin-13 signaling. DR Reactome; R-HSA-75893; TNF signaling. DR Reactome; R-HSA-9942503; Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells). DR Reactome; R-HSA-9968734; Differentiation of Circulating Monocytes. DR SignaLink; P01375; -. DR SIGNOR; P01375; -. DR Agora; ENSG00000232810; -. DR BioGRID-ORCS; 7124; 11 hits in 1165 CRISPR screens. DR ChiTaRS; TNF; human. DR EvolutionaryTrace; P01375; -. DR GeneWiki; Tumor_necrosis_factor-alpha; -. DR GenomeRNAi; 7124; -. DR Pharos; P01375; Tclin. DR PRO; PR:P01375; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; P01375; protein. DR Bgee; ENSG00000232810; Expressed in granulocyte and 90 other cell types or tissues. DR ExpressionAtlas; P01375; baseline and differential. DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL. DR GO; GO:0009897; C:external side of plasma membrane; ISS:BHF-UCL. DR GO; GO:0005576; C:extracellular region; IDA:BHF-UCL. DR GO; GO:0045121; C:membrane raft; IDA:BHF-UCL. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0001891; C:phagocytic cup; ISS:BHF-UCL. DR GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL. DR GO; GO:0055037; C:recycling endosome; ISS:BHF-UCL. DR GO; GO:0005125; F:cytokine activity; IDA:BHF-UCL. DR GO; GO:0140072; F:histone H3K9ac reader activity; IEA:Ensembl. DR GO; GO:0042802; F:identical protein binding; IDA:BHF-UCL. DR GO; GO:0002020; F:protease binding; IPI:BHF-UCL. DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB. DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IDA:BHF-UCL. DR GO; GO:0140374; P:antiviral innate immune response; IDA:UniProt. DR GO; GO:0048143; P:astrocyte activation; NAS:ARUK-UCL. DR GO; GO:0019722; P:calcium-mediated signaling; IEA:Ensembl. DR GO; GO:0007259; P:cell surface receptor signaling pathway via JAK-STAT; ISS:ARUK-UCL. DR GO; GO:1904646; P:cellular response to amyloid-beta; IEA:Ensembl. DR GO; GO:0071479; P:cellular response to ionizing radiation; IDA:BHF-UCL. DR GO; GO:0071316; P:cellular response to nicotine; IDA:UniProtKB. DR GO; GO:0071300; P:cellular response to retinoic acid; IEA:Ensembl. DR GO; GO:0097237; P:cellular response to toxic substance; IEA:Ensembl. DR GO; GO:0071346; P:cellular response to type II interferon; IEA:Ensembl. DR GO; GO:0002439; P:chronic inflammatory response to antigenic stimulus; IMP:BHF-UCL. DR GO; GO:0007623; P:circadian rhythm; IEA:Ensembl. DR GO; GO:0050890; P:cognition; TAS:ARUK-UCL. DR GO; GO:0050966; P:detection of mechanical stimulus involved in sensory perception of pain; IEA:Ensembl. DR GO; GO:0048566; P:embryonic digestive tract development; IEP:DFLAT. DR GO; GO:0072577; P:endothelial cell apoptotic process; IEA:Ensembl. DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:UniProtKB. DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IDA:UniProtKB. DR GO; GO:0006955; P:immune response; IBA:GO_Central. DR GO; GO:0006954; P:inflammatory response; IDA:BHF-UCL. DR GO; GO:0090594; P:inflammatory response to wounding; IDA:UniProt. DR GO; GO:0050901; P:leukocyte tethering or rolling; IDA:BHF-UCL. DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Ensembl. DR GO; GO:0097421; P:liver regeneration; IEA:Ensembl. DR GO; GO:0002281; P:macrophage activation involved in immune response; IEA:Ensembl. DR GO; GO:0001774; P:microglial cell activation; ISS:ARUK-UCL. DR GO; GO:0097527; P:necroptotic signaling pathway; IDA:UniProtKB. DR GO; GO:1900222; P:negative regulation of amyloid-beta clearance; ISS:ARUK-UCL. DR GO; GO:2001234; P:negative regulation of apoptotic signaling pathway; IGI:ARUK-UCL. DR GO; GO:1903347; P:negative regulation of bicellular tight junction assembly; IDA:UniProtKB. DR GO; GO:0120190; P:negative regulation of bile acid secretion; IEA:Ensembl. DR GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IDA:BHF-UCL. DR GO; GO:0061048; P:negative regulation of branching involved in lung morphogenesis; IDA:UniProtKB. DR GO; GO:0002719; P:negative regulation of cytokine production involved in immune response; IDA:BHF-UCL. DR GO; GO:0046325; P:negative regulation of D-glucose import across plasma membrane; IEA:Ensembl. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IEA:Ensembl. DR GO; GO:2001240; P:negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; IDA:BHF-UCL. DR GO; GO:0045599; P:negative regulation of fat cell differentiation; NAS:BHF-UCL. DR GO; GO:0010629; P:negative regulation of gene expression; IDA:UniProtKB. DR GO; GO:0010459; P:negative regulation of heart rate; IEA:Ensembl. DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IDA:BHF-UCL. DR GO; GO:0002037; P:negative regulation of L-glutamate import across plasma membrane; IEA:Ensembl. DR GO; GO:0050995; P:negative regulation of lipid catabolic process; IDA:BHF-UCL. DR GO; GO:0010888; P:negative regulation of lipid storage; NAS:BHF-UCL. DR GO; GO:1902894; P:negative regulation of miRNA transcription; NAS:BHF-UCL. DR GO; GO:0045930; P:negative regulation of mitotic cell cycle; IEA:Ensembl. DR GO; GO:0031642; P:negative regulation of myelination; IEA:Ensembl. DR GO; GO:0050768; P:negative regulation of neurogenesis; TAS:ARUK-UCL. DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; IEA:Ensembl. DR GO; GO:0090324; P:negative regulation of oxidative phosphorylation; IEA:Ensembl. DR GO; GO:0003085; P:negative regulation of systemic arterial blood pressure; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0061044; P:negative regulation of vascular wound healing; IDA:BHF-UCL. DR GO; GO:0045071; P:negative regulation of viral genome replication; IDA:BHF-UCL. DR GO; GO:0045760; P:positive regulation of action potential; IEA:Ensembl. DR GO; GO:1902004; P:positive regulation of amyloid-beta formation; ISS:ARUK-UCL. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:2000334; P:positive regulation of blood microparticle formation; IDA:BHF-UCL. DR GO; GO:0070886; P:positive regulation of calcineurin-NFAT signaling cascade; IDA:MGI. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IDA:UniProtKB. DR GO; GO:0045785; P:positive regulation of cell adhesion; IMP:UniProtKB. DR GO; GO:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; IDA:BHF-UCL. DR GO; GO:0032722; P:positive regulation of chemokine production; IDA:BHF-UCL. DR GO; GO:0001819; P:positive regulation of cytokine production; IDA:BHF-UCL. DR GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; IDA:ARUK-UCL. DR GO; GO:2000573; P:positive regulation of DNA biosynthetic process; IEA:Ensembl. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; NAS:BHF-UCL. DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IBA:GO_Central. DR GO; GO:0031622; P:positive regulation of fever generation; ISS:BHF-UCL. DR GO; GO:0032724; P:positive regulation of fractalkine production; ISS:ARUK-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; IDA:UniProtKB. DR GO; GO:0060252; P:positive regulation of glial cell proliferation; IDA:ARUK-UCL. DR GO; GO:0051798; P:positive regulation of hair follicle development; IEA:Ensembl. DR GO; GO:2000347; P:positive regulation of hepatocyte proliferation; IEA:Ensembl. DR GO; GO:0034116; P:positive regulation of heterotypic cell-cell adhesion; IDA:BHF-UCL. DR GO; GO:0002639; P:positive regulation of immunoglobulin production; IEA:Ensembl. DR GO; GO:0050729; P:positive regulation of inflammatory response; TAS:ARUK-UCL. DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IDA:ARUK-UCL. DR GO; GO:0032741; P:positive regulation of interleukin-18 production; IEA:Ensembl. DR GO; GO:0150129; P:positive regulation of interleukin-33 production; IDA:ARUK-UCL. DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:ARUK-UCL. DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:BHF-UCL. DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:BHF-UCL. DR GO; GO:1904999; P:positive regulation of leukocyte adhesion to arterial endothelial cell; IDA:BHF-UCL. DR GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; IDA:BHF-UCL. DR GO; GO:0010744; P:positive regulation of macrophage derived foam cell differentiation; IDA:BHF-UCL. DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:BHF-UCL. DR GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; IDA:BHF-UCL. DR GO; GO:1902895; P:positive regulation of miRNA transcription; IDA:BHF-UCL. DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; IEA:Ensembl. DR GO; GO:0071677; P:positive regulation of mononuclear cell migration; NAS:BHF-UCL. DR GO; GO:0150078; P:positive regulation of neuroinflammatory response; TAS:ARUK-UCL. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:ARUK-UCL. DR GO; GO:1902565; P:positive regulation of neutrophil activation; IEA:Ensembl. DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IDA:BHF-UCL. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IDA:UniProtKB. DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IDA:BHF-UCL. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; ISS:ARUK-UCL. DR GO; GO:0071803; P:positive regulation of podosome assembly; IDA:BHF-UCL. DR GO; GO:0043068; P:positive regulation of programmed cell death; IDA:UniProtKB. DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:AgBase. DR GO; GO:2000010; P:positive regulation of protein localization to cell surface; IDA:BHF-UCL. DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; ISS:ARUK-UCL. DR GO; GO:0051222; P:positive regulation of protein transport; IDA:BHF-UCL. DR GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IDA:BHF-UCL. DR GO; GO:0043243; P:positive regulation of protein-containing complex disassembly; IDA:BHF-UCL. DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IDA:BHF-UCL. DR GO; GO:0050806; P:positive regulation of synaptic transmission; ISS:ARUK-UCL. DR GO; GO:1901647; P:positive regulation of synoviocyte proliferation; IDA:ARUK-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:1904707; P:positive regulation of vascular associated smooth muscle cell proliferation; IEA:Ensembl. DR GO; GO:0060557; P:positive regulation of vitamin D biosynthetic process; IDA:BHF-UCL. DR GO; GO:0072659; P:protein localization to plasma membrane; IDA:UniProtKB. DR GO; GO:0043122; P:regulation of canonical NF-kappaB signal transduction; IDA:BHF-UCL. DR GO; GO:2000351; P:regulation of endothelial cell apoptotic process; IMP:ARUK-UCL. DR GO; GO:1903140; P:regulation of establishment of endothelial barrier; IDA:UniProtKB. DR GO; GO:0045598; P:regulation of fat cell differentiation; ISS:ARUK-UCL. DR GO; GO:0050796; P:regulation of insulin secretion; IDA:BHF-UCL. DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IDA:BHF-UCL. DR GO; GO:0050807; P:regulation of synapse organization; ISS:ARUK-UCL. DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; TAS:ARUK-UCL. DR GO; GO:1905242; P:response to 3,3',5-triiodo-L-thyronine; IEA:Ensembl. DR GO; GO:0014823; P:response to activity; IEA:Ensembl. DR GO; GO:0001975; P:response to amphetamine; IEA:Ensembl. DR GO; GO:0046677; P:response to antibiotic; IEA:Ensembl. DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl. DR GO; GO:0009750; P:response to fructose; IEA:Ensembl. DR GO; GO:0051384; P:response to glucocorticoid; IDA:BHF-UCL. DR GO; GO:1990268; P:response to gold nanoparticle; IEA:Ensembl. DR GO; GO:0140460; P:response to Gram-negative bacterium; IEA:Ensembl. DR GO; GO:1904880; P:response to hydrogen sulfide; IEA:Ensembl. DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl. DR GO; GO:0035900; P:response to isolation stress; IEA:Ensembl. DR GO; GO:1902065; P:response to L-glutamate; IEA:Ensembl. DR GO; GO:0036005; P:response to macrophage colony-stimulating factor; IEA:Ensembl. DR GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl. DR GO; GO:1905235; P:response to quercetin; IEA:Ensembl. DR GO; GO:1904638; P:response to resveratrol; IEA:Ensembl. DR GO; GO:0009651; P:response to salt stress; TAS:BHF-UCL. DR GO; GO:0009615; P:response to virus; IDA:BHF-UCL. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0003009; P:skeletal muscle contraction; IEA:Ensembl. DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; IEA:Ensembl. DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IDA:BHF-UCL. DR GO; GO:0010573; P:vascular endothelial growth factor production; IDA:UniProtKB. DR GO; GO:0042311; P:vasodilation; IEA:Ensembl. DR CDD; cd00184; TNF; 1. DR FunFam; 2.60.120.40:FF:000007; Tumor necrosis factor; 1. DR Gene3D; 2.60.120.40; -; 1. DR InterPro; IPR006053; TNF. DR InterPro; IPR002959; TNF_alpha. DR InterPro; IPR021184; TNF_CS. DR InterPro; IPR006052; TNF_dom. DR InterPro; IPR008983; Tumour_necrosis_fac-like_dom. DR PANTHER; PTHR11471:SF23; TUMOR NECROSIS FACTOR; 1. DR PANTHER; PTHR11471; TUMOR NECROSIS FACTOR FAMILY MEMBER; 1. DR Pfam; PF00229; TNF; 1. DR PRINTS; PR01234; TNECROSISFCT. DR PRINTS; PR01235; TNFALPHA. DR SMART; SM00207; TNF; 1. DR SUPFAM; SSF49842; TNF-like; 1. DR PROSITE; PS00251; THD_1; 1. DR PROSITE; PS50049; THD_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Cytokine; Direct protein sequencing; KW Disulfide bond; Glycoprotein; Lipoprotein; Membrane; Myristate; KW Phosphoprotein; Proteomics identification; Reference proteome; Secreted; KW Signal-anchor; Transmembrane; Transmembrane helix. FT CHAIN 1..233 FT /note="Tumor necrosis factor, membrane form" FT /id="PRO_0000034423" FT CHAIN 1..39 FT /note="Intracellular domain 1" FT /id="PRO_0000417231" FT CHAIN 1..35 FT /note="Intracellular domain 2" FT /id="PRO_0000417232" FT CHAIN 50..? FT /note="C-domain 1" FT /id="PRO_0000417233" FT CHAIN 52..? FT /note="C-domain 2" FT /id="PRO_0000417234" FT CHAIN 77..233 FT /note="Tumor necrosis factor, soluble form" FT /evidence="ECO:0000269|PubMed:8631363, FT ECO:0000305|PubMed:9034191" FT /id="PRO_0000034424" FT TOPO_DOM 1..35 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 36..56 FT /note="Helical; Signal-anchor for type II membrane protein" FT /evidence="ECO:0000255" FT TOPO_DOM 57..233 FT /note="Extracellular" FT /evidence="ECO:0000255" FT DOMAIN 88..233 FT /note="THD" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01387" FT SITE 35..36 FT /note="Cleavage; by SPPL2A or SPPL2B" FT /evidence="ECO:0000269|PubMed:16829951" FT SITE 39..40 FT /note="Cleavage; by SPPL2A or SPPL2B" FT /evidence="ECO:0000269|PubMed:16829951" FT SITE 49..50 FT /note="Cleavage; by SPPL2A or SPPL2B" FT /evidence="ECO:0000269|PubMed:16829951" FT SITE 51..52 FT /note="Cleavage; by SPPL2A or SPPL2B" FT /evidence="ECO:0000269|PubMed:16829951" FT SITE 76..77 FT /note="Cleavage; by ADAM17" FT /evidence="ECO:0000269|PubMed:9034191" FT MOD_RES 2 FT /note="Phosphoserine; by CK1" FT /evidence="ECO:0000305" FT LIPID 19 FT /note="N6-myristoyl lysine" FT /evidence="ECO:0000269|PubMed:1402651, FT ECO:0000269|PubMed:23552949" FT LIPID 20 FT /note="N6-myristoyl lysine" FT /evidence="ECO:0000269|PubMed:1402651, FT ECO:0000269|PubMed:23552949" FT CARBOHYD 80 FT /note="O-linked (GalNAc...) serine; in soluble form" FT /evidence="ECO:0000269|PubMed:8631363" FT DISULFID 145..177 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01387, FT ECO:0000269|PubMed:16284179, ECO:0007744|PDB:2AZ5" FT VARIANT 84 FT /note="P -> L (in dbSNP:rs4645843)" FT /evidence="ECO:0000269|Ref.13" FT /id="VAR_019378" FT VARIANT 94 FT /note="A -> T (in dbSNP:rs1800620)" FT /id="VAR_011927" FT MUTAGEN 19..20 FT /note="KK->RR: Abolished myristoylation." FT /evidence="ECO:0000269|PubMed:23552949" FT MUTAGEN 105 FT /note="L->S: Low activity." FT /evidence="ECO:0000269|PubMed:2009860" FT MUTAGEN 108 FT /note="R->W: Biologically inactive." FT /evidence="ECO:0000269|PubMed:2009860" FT MUTAGEN 112 FT /note="L->F: Biologically inactive." FT /evidence="ECO:0000269|PubMed:2009860" FT MUTAGEN 160 FT /note="A->V: Biologically inactive." FT /evidence="ECO:0000269|PubMed:2009860" FT MUTAGEN 162 FT /note="S->F: Biologically inactive." FT /evidence="ECO:0000269|PubMed:2009860" FT MUTAGEN 167 FT /note="V->A,D: Biologically inactive." FT /evidence="ECO:0000269|PubMed:2009860" FT MUTAGEN 222 FT /note="E->K: Biologically inactive." FT /evidence="ECO:0000269|PubMed:2009860" FT CONFLICT 63 FT /note="F -> S (in Ref. 5; AAA61198)" FT /evidence="ECO:0000305" FT CONFLICT 84..86 FT /note="PSD -> VNR (in Ref. 17; AAF71992)" FT /evidence="ECO:0000305" FT CONFLICT 183 FT /note="E -> R (in Ref. 16; AAC03542)" FT /evidence="ECO:0000305" FT HELIX 32..35 FT /evidence="ECO:0007829|PDB:7ASY" FT HELIX 37..53 FT /evidence="ECO:0007829|PDB:7ASY" FT HELIX 82..85 FT /evidence="ECO:0007829|PDB:7JRA" FT STRAND 89..94 FT /evidence="ECO:0007829|PDB:9OJO" FT STRAND 96..98 FT /evidence="ECO:0007829|PDB:5M2I" FT STRAND 99..101 FT /evidence="ECO:0007829|PDB:2E7A" FT STRAND 104..108 FT /evidence="ECO:0007829|PDB:9OJO" FT STRAND 112..114 FT /evidence="ECO:0007829|PDB:9OJO" FT STRAND 118..120 FT /evidence="ECO:0007829|PDB:9OJO" FT STRAND 123..125 FT /evidence="ECO:0007829|PDB:9OJO" FT STRAND 130..144 FT /evidence="ECO:0007829|PDB:9OJO" FT STRAND 146..148 FT /evidence="ECO:0007829|PDB:2ZPX" FT STRAND 152..160 FT /evidence="ECO:0007829|PDB:9OJO" FT STRAND 163..174 FT /evidence="ECO:0007829|PDB:9OJO" FT STRAND 177..179 FT /evidence="ECO:0007829|PDB:1A8M" FT STRAND 182..185 FT /evidence="ECO:0007829|PDB:4TSV" FT STRAND 189..202 FT /evidence="ECO:0007829|PDB:9OJO" FT STRAND 207..213 FT /evidence="ECO:0007829|PDB:9OJO" FT HELIX 215..217 FT /evidence="ECO:0007829|PDB:9OJO" FT TURN 221..224 FT /evidence="ECO:0007829|PDB:7TA6" FT STRAND 225..232 FT /evidence="ECO:0007829|PDB:9OJO" SQ SEQUENCE 233 AA; 25644 MW; 3DF90F96C9031FFE CRC64; MSTESMIRDV ELAEEALPKK TGGPQGSRRC LFLSLFSFLI VAGATTLFCL LHFGVIGPQR EEFPRDLSLI SPLAQAVRSS SRTPSDKPVA HVVANPQAEG QLQWLNRRAN ALLANGVELR DNQLVVPSEG LYLIYSQVLF KGQGCPSTHV LLTHTISRIA VSYQTKVNLL SAIKSPCQRE TPEGAEAKPW YEPIYLGGVF QLEKGDRLSA EINRPDYLDF AESGQVYFGI IAL //